The amount of energy expended as heat can be a major determinant of the degree of obesity in man and other animals. Heat production, in turn, is affected by both genetic and environmental factors. One major hypothesis to be tested is that neonatal overnutrition sets the "metabolic stage" for the development of obesity by altering thermic responses to feeding. We will examine mechanism(s) underlying altered thermogenesis in obesity in 2 animal models: genetically lean rats overfed during suckling (diet-induced obesity) and genetically obese rats (fa/fa). The first experiments will use 8 day rats to determine if preobese fa/fa pups show blunted thermic responses to feeding as they do cold and, if these responses are associated with alterations in the sympathetic nervous system (as measured by altered sympathetic input to brown adipose tissue (BAT), the major site of nonshiverig/nonmuscle regulatory heat production), or with metabolic alterations in BAT thermogenic pathways, or with altered monoamine neurotransmitter turnover in the ventromedial hypothalamus (VMH) and the paraventricular nucleus (PVN). Parallel studies will be done in genetically lean 8 day rats overfed during suckling. Such pups show enhanced cold-induced thermogenesis, but still become obese. Thus, it is imporant to determine if their thermic response to feeding is blunted; and how mechanisms associated with their responses differ from those of genetically obese pups and of lean control pups. The second major group of experiments will use 10-12 wk obese rats to evaluate mechanisms underlying the anti-obesity effects of adrenalectomy (ADX). ADX normalizes BAT thermogenic capacity in genetically obese rats. It is unclear if this occurs in our diet-induced obese model. Sympathetic input to BAT and monoamine turnover in the VMH and PVN will be examined in fa/fa rats and in genetically lean rats overfed during suckling. Techniques utilized will include measurements of: oxygen consumption; body composition; serotonin, dopamine, and their metabolites in selected brain areas using HPLC (to estimate serotonin and dopamine turnover); brain and BAT norepinephrine (NE) levels after tyrosine hydroxylase inhibition (to estimate NE turnover in selected brain areas and sympathetic input to BAT); BAT succinic dehydrogenase activity; BAT mitochondrial GDP binding (an in vitro index of BAT thermogenic capacity); and white adipocyte size and number. These studies will provide basic information on hormonal and neural changes associated with (and perhaps resulting in) the altered thermogenesis accompanying development of obesity in neonates and adults. They will also help elucidate mechanism(s) whereby some animals conserve excess calories while others dissipate them as heat. This understanding will ultimately lead to more rational strategies for prevention and treatment of human obesity.